Intracellular receptors (IRs) form a class of structurally-related genetic regulators scientists have named “ligand dependent transcription factors” (R. M. Evans, Science, 240:889, 1988). Sex steroid hormone receptors are a recognized subset of the IRs, including androgen receptor (AR), progesterone receptor (PR) and estrogen receptor (ER). Regulation of a gene by such factors requires both the receptor itself and a corresponding ligand, which has the ability to selectively bind to the receptor in a way that affects gene transcription.
The natural hormones for sex steroid receptors have been known for a long time, such as testosterone for AR and progesterone for PR. A compound that binds to a receptor and mimics the effect of the native hormone is referred to as an “agonist”, while a compound that inhibits the effect of the native hormone is called an “antagonist.” The term “modulators” refers to compounds that are agonists, partial agonists or antagonists.
Synthetic female sex hormones have been widely used in oral contraception, hormone replacement therapy and the treatment of hormone-dependent disorders. The development of new generations of selective estrogen receptor modulators (SERMs) significantly improved women's health. On the other hand, similar hormone therapy for men has not been fully explored due to lack of availability of selective, orally administered, safe agents.
A group of hydroquinoline derivatives was recently described as AR modulators (e.g., U.S. Pat. No. 5,696,130). This group of AR modulators was developed by using cell-based high-throughput assays, termed cotransfection assays.
The entire disclosures of the publications and references referred to herein are incorporated by reference herein and are not admitted to be prior art.